title: Epstein-Barr virus coinfection in children boosts cytomegalovirus-induced differentiation of natural killer cells.
abstract: During childhood, infections with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) can occur in close temporal proximity. Active, as well as latent, CMV infection is associated with enlarged subsets of differentiated natural killer (NK) and cytotoxic T cells. How EBV infection may influence CMV-driven immune differentiation is not known. We found that EBV coinfection selectively influenced the NK cell compartment of CMV-seropositive (CMV(+)) children. Coinfected children had significantly higher proportions of peripheral-blood NKG2C(+) NK cells than CMV(+) EBV(-) children. Ex vivo NK cell degranulation after target cell stimulation and plasma IL-15 levels were significantly higher in CMV(+) children. EBV coinfection was related to the highest levels of plasma interleukin-15 (IL-15) and IL-12p70. Remarkably, in vitro EBV infection of peripheral blood mononuclear cells (PBMC) from EBV(-) CMV(+) children increased NKG2C(+) NK cell proportions. A similar tendency was seen in cocultures of PBMC with EBV(+) lymphoblastoid B-cell lines (LCL) and IL-15. After K562 challenge, NKG2C(+) NK cells excelled in regard to degranulation and production of gamma interferon, regardless of whether there was previous coculture with LCL. Taken together, our data suggest that dual latency with these herpesviruses during childhood could contribute to an in vivo environment supporting differentiation and maintenance of distinct NK cell populations. This viral imprint may affect subsequent immune responses through altered distributions of effector cells.
authors.affiliation: Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Shanie
authors.initials: S
authors.lastname: Saghafian-Hedengren
authors.forename: Ebba
authors.initials: E
authors.lastname: Sohlberg
authors.forename: Jakob
authors.initials: J
authors.lastname: Theorell
authors.forename: Claudia
authors.initials: C
authors.lastname: Carvalho-Queiroz
authors.forename: Noémi
authors.initials: N
authors.lastname: Nagy
authors.forename: Jan-Olov
authors.initials: JO
authors.lastname: Persson
authors.forename: Caroline
authors.initials: C
authors.lastname: Nilsson
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.forename: Eva
authors.initials: E
authors.lastname: Sverremark-Ekström
mesh_terms: D002454:Cell Differentiation; D002675:Child, Preschool; D015331:Cohort Studies; D060085:Coinfection / Q000276:immunology* / Q000821:virology; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000503:physiopathology* / Q000821:virology; D005260:Female; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008297:Male
chemical_list: D019409:Interleukin-15; D018664:Interleukin-12